Aortic valve replacement (AVR) is the only life-saving treatment for patients with severe symptomatic aortic stenosis. Bioprosthetic valves are used in 90% of AVRs because they do not require lifelong anticoagulation. The major limitation of bioprosthetic valves is their limited durability compared to mechanical valves. In addition, bioprosthetic valves still carry a 2-3% risk of symptomatic valve thrombosis, stroke, and thromboembolism in the first 30 days after implantation, and a 1% annual risk thereafter. The risk of subclinical valve thrombosis is around 10% at 30 days and 25% at 1 year, and prevention of subclinical valve thrombosis is hypothesized to reduce the risk of clinical thrombotic events and perhaps even improve valve durability, although high-quality evidence is lacking. This doctoral thesis comprises 7 chapters of varied methodology that summarize the evidence behind current recommendations for antithrombotic therapy after bioprosthetic AVR, identify evidence gaps, and present the design a randomized trial that aims to address some of these evidence gaps. Chapter 1 introduces each included study with a brief summary. Chapter 2 is a narrative review summarizing guideline recommendation for antithrombotic therapy after bioprosthetic AVR and the evidence upon which they are based. Chapter 3 is an observational study describing antithrombotic prescribing practices in the VISION Cardiac Surgery cohort study. Chapter 4 is a systematic review and network meta-analysis of randomized studies of antithrombotic therapy after transcatheter aortic valve replacement. Chapter 5 is a systematic review and meta-analysis of randomized and observational studies of subclinical valve thrombosis. Chapter 6 presents the design and rationale of a feasibility trial of direct oral anticoagulants versus vitamin K antagonists in patients with a new surgical bioprosthetic AVR and atrial fibrillation. Chapter 7 discusses the implications, limitations, and future avenues of the research presented in this doctoral thesis. / Thesis / Doctor of Philosophy (PhD) / More than 10,000 Canadians require aortic valve replacement each year. Bioprosthetic valves (made out of cow or pig tissue) are often preferred over mechanical valves (made out of metal) because the risk of blood clots forming on the valve or causing a stroke is lower. The disadvantage of bioprosthetic valves is that they can wear out and require re-replacement. The reason why bioprosthetic valves wear out is uncertain, but it may be related to small blood clots on the valve that are only detectable on a CT scan. This doctoral thesis explores the use of blood thinners for patients with bioprosthetic aortic valve replacement. Ideally, blood thinners would be able to prevent blood clots and stroke, and to improve the durability of bioprosthetic valves, without causing too much bleeding. The thesis reviews the available evidence, identifies unanswered questions, and ends with a proposal for a study to generate new data.

Background: Aortic valve insufficiency (AI) at the time of left ventricular assist device (LVAD) insertion needs to be corrected, however there is little known about how to manage bioprosthetic valvular AI. Case presentation: A 55-year-old female with dilated cardiomyopathy who previously had a bioprosthetic aortic valve replacement needed a LVAD as a bridge to transplant. Her left ventricular ejection fraction was 10% and had mild to moderate transvalvular AI. She underwent a HeartWare HVAD insertion along with aortic valvular coaptation stitch repair (Park's stitch) to the bioprosthetic valve. Conclusion: Her AI improved to trivial with minimal ejection through the bioprosthetic valve. She was transplanted 6 months following the surgery. A Park's stitch to the bioprosthetic aortic valve with more than mild AI might be a good option for bridge to transplant patient.

Evidence suggests that there is an immunological response of the recipient to xenograft bioprosthetic heart valves. Information on the impact of HMG-CoA reductase inhibitors (statins) and their anti-inflammatory properties on bioprosthetic valve failure remains limited. We sought to examine the efficacy of statin therapy in a rodent model of bioprosthetic valve implantation. To mimic the human scenario, fresh or glutaraldehyde-fixed aortic valve root conduits from Lewis rats or Hartley guinea pigs were microsurgically implanted intravascularly into the infra-renal aorta of Lewis rats. The syngeneic control group consisted of a fresh rat valve conduit implanted into a rat. The xenogeneic control group consisted of a glutaraldehyde-fixed guinea pig valve conduit implanted into a rat. Treatment groups consisted of xenogeneic groups treated with either daily steroids or statins. Overall, steroid treatment attenuated the inflammatory response observed within the xenogeneic glutaraldehyde-fixed valve conduits. Treatment with statins did not decrease this inflammatory response.

Evidence suggests that there is an immunological response of the recipient to xenograft bioprosthetic heart valves. Information on the impact of HMG-CoA reductase inhibitors (statins) and their anti-inflammatory properties on bioprosthetic valve failure remains limited. We sought to examine the efficacy of statin therapy in a rodent model of bioprosthetic valve implantation. To mimic the human scenario, fresh or glutaraldehyde-fixed aortic valve root conduits from Lewis rats or Hartley guinea pigs were microsurgically implanted intravascularly into the infra-renal aorta of Lewis rats. The syngeneic control group consisted of a fresh rat valve conduit implanted into a rat. The xenogeneic control group consisted of a glutaraldehyde-fixed guinea pig valve conduit implanted into a rat. Treatment groups consisted of xenogeneic groups treated with either daily steroids or statins. Overall, steroid treatment attenuated the inflammatory response observed within the xenogeneic glutaraldehyde-fixed valve conduits. Treatment with statins did not decrease this inflammatory response.

Novel biomaterials provide a spectrum of possibilities. They can be engineered in different forms to understand how they would perform as different bioprosthetic conduits. Bacterial cellulose membranes may be suitable candidates as prosthetic valve leaflets in valve replacement surgeries due to their functional properties (hemodynamics, resistant to thrombosis). Biomaterials used for most bioprosthetic heart valves are cut, trimmed and sutured. A major challenge for the bi-leaflet configuration is that the cutting and suturing of biopolymers fabricated as sheets into a cylindrical form increases failure risk due to greater number of suture points and irregular coaptation. The objective was to culture the bacterial cellulose membrane as a continuous cylindrical construct and evaluate its mechanical properties. Various design features of the fabrication process such as culturing media and the hollow carrier-mandrel characteristics were evaluated. A comparative study of how bacterial cellulose grows on different hollow carrier membranes was conducted and thin smooth surface silicone tubes fabricated in the lab were found to be most suitable. A bioreactor for culturing cylindrical bacterial cellulose tubes on the outer surface of the hollow carrier was designed and fabricated. The mechanical properties of the fabricated tubes, specifically, their tensile strength, flexure, suture retention and tear resistance were characterized. Mechanical characterization studies showed the cylindrical bacterial cellulose tubes to be anisotropic, with preferential properties in the longitudinal (axial) direction of the tube. Preliminary results show that cylindrical bacterial cellulose tubes can be a promising candidate for use in prosthetic valve conduits.

Thesis (MScEng)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Bioprosthetic heart valves (BHVs) for transcatheter aortic valve implantation (TAVI) have been rapidly developing over the last decade since the first valve replacement using the TAVI technique. TAVI is a minimally invasive valve replacement procedure offering lifesaving treatment to patients who are denied open heart surgery. The biomedical engineering research group at Stellenbosch University designed a 19 mm balloon expandable BHV for TAVI in 2007/8 for testing in animal trials. In the current study the valve was enlarged to 23 mm and 26 mm diameters. A finite element analysis was performed to aid in the design of the stents. New stencils were designed and manufactured for the leaflets using Thubrikar‟s equations as a guide. The 23 mm valve was manufactured and successfully implanted into two sheep. Fluid structure interaction (FSI) simulations constitute a large portion of this thesis and are being recognized as an important tool in the design of BHVs. Furthermore, they provide insight into the interaction of the blood with the valve, the leaflet dynamics and valve hemodynamic performance. The complex material properties, pulsating flow, large deformations and coupling of the fluid and the physical structure make this one of the most complicated and difficult research areas within the body. The FSI simulations, of the current valve design, were performed using a commercial programme called MSC.Dytran. A validation study was performed using data collected from a cardiac pulse duplicator. The FSI model was validated using leaflet dynamics visualisation and transvalvular pressure gradient comparison. Further comparison studies were performed to determine the material model to be used and the effect of leaflet free edge length and valve diameter on valve performance. The results from the validation study correlated well, considering the limitations that were experienced. However, further research is required to achieve a thorough validation. The comparative studies indicated that the linear isotropic material model was the most stable material model which could be used to simulate the leaflet behaviour. The free edge length of the leaflet affects the leaflet dynamics but does not greatly hinder its performance. The hemodynamic performance of the valve improves with an increase in diameter and the leaflet dynamics perform well considering the increased surface area and length. Many limitations in the software prevented more accurate material models and flow initiation to be implemented. These limitations significantly restricted the research and confidence in the results. Further investigation regarding the implementation of FSI simulations of a heart valve using the commercial software is recommended. / AFRIKAANSE OPSOMMING: Bio-prostetiese hartkleppe (Bioprosthetic Heart Valves - BHVs) wat gebruik word vir transkateter aortaklep-inplantings (Transcatheter Aortic Valve Implantation - TAVI) het geweldig vinnige ontwikkeling getoon in die afgelope tien jaar sedert die eerste klepvervanging wat van die TAVI prosedure gebruik gemaak het. TAVI is ʼn minimaal indringende klepvervangingsprosedure wat lewensreddende behandeling bied aan pasiënte wat ope-hart sjirurgie geweier word. Die Biomediese Ingenieurswese Navorsingsgroep (BERG) by Stellenbosch Universiteit het in 2007/8 ʼn 19 mm ballon-uitsetbare BHV vir TAVI ontwerp vir eksperimente met diere, en hierdie tesis volg op die vorige projekte. In die huidige studie is die klep vergroot na 23 mm en 26 mm in deursnee. ʼn Eindige element analise is gedoen om by te dra tot die ontwerp van die rekspalke vir die klep. Nuwe stensils is ontwerp en vervaardig vir die klepsuile, deur gebruik te maak van Thubrikar se vergelykings. Die 23 mm klep is vervaardig en suksesvol in twee skape ingeplant. Vloeistruktuur interaksie (Fluid Structure Interaction (FSI)) simulasies vorm ‟n groot deel van die tesis en word gesien as ʼn noodsaaklike hulpmiddel in die ontwerp van BHVs. Die simulasies verskaf ook insig in die interaksie van die bloed met die klep, die klepsuil-dinamika en die klep se hemodinamiese werkverrigting. Die komplekse materiaal eienskappe, polsende vloei, grootskaalse vervorming, die verbinding van die vloeistof en die fisiese struktuur maak van hierdie een van die mees gekompliseerde voorwerpe om te simuleer. Die FSI simulasies van die huidige ontwerp, is uitgevoer deur van kommersiële sagteware, MSC.Dytran, gebruik te maak. ʼn Geldigheidstudie wat data gebruik het vanaf die hartklop-nabootser, is uitgevoer. Die FSI model word geverifieer deur klepsuil dinamika visualisering en ʼn vergelyking van die drukgradiënt gebruik te maak. Verdere vergelykende studies is uitgevoer om te bepaal watter materiaal model om te gebruik, asook die uitwerking van die klepsuil-vrye rand en klepdeursnee op die klep se werkverrigting. Die resultate van die studie korreleer goed, in ag genome die beperkings wat ervaar is. Verdere navorsing is egter nodig vir ʼn volledige geldigheidstudie. Vergelykende studies het getoon dat die liniêre isotropiese materiaalmodel die meer stabiele materiaalmodel is wat kan gebruik word om klepsuilgedrag te simuleer. Die vrye-rand lengte van die klepsuil affekteer die dinamika van die klepsuil, maar belemmer nie die werkverrigting grootliks nie. Die hemodinamiese werkverrigting van die klep verbeter met die toename in deursnee en die klepsuil-dinamika vertoon goed in ag genome die verhoogde oppervlak area en lengte. Die vele beperkings in die sagteware het die implementering van meer akkurate materiaalmodelle verhoed. Hierdie beperkings het ʼn verminderde vertroue in die resultate tot gevolg gehad. Verdere ondersoek rakende die implementering van die FSI simulasies van ʼn hartklep deur kommersieel beskikbare sagteware te gebruik, word aanbevel.